title: A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT.
abstract: A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 μM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity.
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa.
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Zishiri
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.forename: Robert
authors.initials: R
authors.lastname: Summers
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; D008744:Methylamines; C559782:N-benzyl-N-methyl-1-phenylmethanamine; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine